As an example of problematic clinical heterogeneity and its impact upon the utility of animal modelling, let us consider the altered stress responsiveness and ‘hypercortisolism’ that has been widely considered as one of the fundamental neurobiological abnormalities of depression (Reus, 1985). This is an area of study that has virtually dominated the modelling literature since Seligman and colleagues described the phenomenon of ‘learned helplessness’ (Overmier and Seligman, 1967; Seligman et al., 1968). Yet, for such a dominant target for physiological modelling, how secure are the findings of altered corticosteroid function in depression? If we are to develop a valid animal model based upon perturbed corticosteroid function as a core aspect of the popular stress/diathesis hypothesis of depression, surely we must be confident that such perturbation is a reliable feature of the clinical presentation labelled depression? Simplified, the popular hypothesis is that environmental (or psychosocial) stress impacts upon vulnerable individuals, eliciting pathological reactivity of the key neuroendocrine ‘stress–response’ system, the hypothalamo– pituitary–adrenal (HPA) axis, with excessive production of cortisol. This, in turn, is believed to modify functioning in key brain circuitry to generate the behavioural and cognitive symptoms of depression (Nemeroff, 1988). However, although intuitively attractive, this is likely to be a gross oversimplification. Using the relative strictures of DSM to recruit subjects, research populations of depressed subjects show remarkable heterogeneity of neuroendocrine function. The proportion of individuals demonstrating HPA-axis abnormalities during acute depression may be as low as 35%, with such abnormalities being unable to differentiate between ‘different’ subtypes of depression (melancholic, endogenous, or psychotic) (Stokes et al., 1984). Similar endocrine changes have been described in patients with quite different diagnoses—substance misuse (Contoreggi et al., 2003), Alzheimer’s Disease (Martignoni et al., 1990), and Post-Traumatic Stress Disorder (Smith et al., 1989), for example. Indeed, both Stokes et al. (1984) and more recent studies have found that the manic phase of Bipolar Disorder, a profoundly different abnormality of mental state and behaviour, is associated with very similar frequency and severity of neuroendocrine dysregulation. Taking a broad overview of the relationship between environmental/psychosocial stress, corticosteroid regulation and depression, Strickland et al. (2002) studied a ‘real world’ community sample and found that, although welldefined adverse life events were associated with increased cortisol production (as estimated by salivary measures), depression was not. In fact, these large scale, carefully collected data were eventually summarised by the authors as “.incompatible with the widely held theory that stress predisposes to depression through its effects on the hypothalamic–pituitary–adrenal (HPA) axis” (Strickland and Deakin, 2002). This is not to suggest, of course, that pre-existing HPA-axis abnormalities may not represent a major contributory factor in the genesis of some severe forms of depression.
Stress responsiveness and chronic depression
Compounding matters, Watson and colleagues recently examined the neuroendocrine status of 29 patients meeting criteria for a diagnosis of chronic depression (an episode lasting O24 months) using the sensitive dexamethasone/ corticotropin releasing hormone (dex/CRH) test and the dexamethasone suppression test (DST) to establish whether HPA-axis abnormalities were present in this clinically important, understudied and challenging population. Contrary to expectations, neither the cortisol response to the classical HPA probe test, the DST, nor the dex/CRH test responses differed significantly between the patients and matched controls. These data prompted the authors to conclude that, entirely contrary to expectations, HPA-axis function does not appear to be overtly abnormal in patients with chronic depression (Watson et al., 2002). This may suggest that any HPA-axis abnormalities presenting during an acute depressive resolve, despite the persistence of affective symptoms. If correct, this is potentially very important for the development of sophisticated theories linking neuroendocrine function with the cognitive and behavioural features of depression. Alternatively, the authors offered the intriguing speculation that it may be a sub-group of depressed patients without HPA dysfunction during the acute phase of illness that are most vulnerable to develop chronic, treatment refractory form of illness. Potentially, this may encourage the view that acute severe depression (with HPA-axis dysfunction) represents a pathology that is relatively distinguishable from chronic depression, despite the many superficial similarities in symptoms and other clinical features. In light of these findings, we therefore pose two questions: if depression is infrequently (or even rarely) a consequence of sustained hypercortisolism, what is the biology of the relationship between psychosocial adversity and depression? Also, what is the validity and relevance of the wealth of studies modelling such processes in animals where the focus is almost exclusively on corticosteroid function and regulation?